The present application is related to U.S. Pat. No. 60/023,944, filed Aug. 14, 1996, the content of which is hereby incorporated by reference.
The present invention is concerned with a process for synthesizing intermediates for compounds which inhibit the protease encoded by human immunodeficiency virus (HIV), and in particular certain oligopeptide analogs, such as Compound J in the Examples below. These compounds are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). These compounds are also useful for inhibiting renin and other proteases.
The inventions described herein concern the conversion of indene to (2S)-amino-(1R)-indanol as illustrated by the following Scheme I. ##STR1##
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N. E. et al., Proc. Nat'l Acad. Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.
The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame Ratner, L. et al., Nature, 313, 277 (1985)!. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an HIV protease Toh, H. et al., EMBO J., 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567 (1986); Pearl, L. H. et al., Nature, 329, 351 (1987)!. The end product compounds, including certain oligopeptide analogs that can be made from the novel intermediates and processes of this invention, are inhibitors of HIV protease, and are disclosed in EPO 541,168, which published on May 12, 1993. See, for example, Compound J therein, also illustrated in the Examples below.
The present application discloses an improved process to make, in substantial stereoisomeric purity, 1 (S)-amino-2(R)-hydroxy indan of the structure ##STR2## which is a sidechain group of Compound J, which is a potent inhibitor of HIV protease.
Previous attempts at synthesis involve inefficient production of the racemate 1 (.+-.)-amino-2(.+-.) hydroxy indan from the racemic indene oxide. Other attempts at synthesis involve bioconversion of indene with a fungal haloperoxidase to give predominantly trans-(2S, 1 S)-bromoindanol, which is then subjected to various chemical steps to give (1S)-amino-(2R)-indanol. Another bioconversion process involves contacting toluene dioxygenase with indene to give a cis-indandiol, which by chemical process affords (1S)-amino-(2R)-indanol. Still other attempts at synthesis relate to chemical synthesis with racemic epoxidation as an intermediate step, followed by resolution with L-tartaric acid.
The present invention provides needed improved alternatives. In the processes of the present invention, the tartaric acid resolution step is eliminated by combining stereoselective bio-oxidation of substrate indene to trans -(1 (R),2R)-indandiol. Further chemical treatment gives (1S)-amino-(2R)-indandiol, e.g. treatment with a nitrile in the presence of aqueous acid according to the Ritter reaction, followed by either reverse ion pair extraction or cation exchange chromatography.
In the processes of the present invention, indene is converted by the action of the enzyme monooxygenase (and perhaps other enzymatic activities, e.g., epoxide hydrolase) to a mixture of trans indandiols containing predominantly the desired (1R,2R) stereoisomer. The desired (1R,2R) stereoisomer is isolated using purification steps, e.g., adsorption, extraction, crystallization to yield substantially pure crystallized trans(1R,2R)-indandiol.
An enantiomeric excess of over about 99% (from indene to the substantially pure trans-(1R,2R)-indandiol) is typical of the processes of the present invention.